Converging lines of evidence point to the melanocortins (MC) as pivotal players in the regulation of food intake and body weight. Central to this research effort has been understanding how two endogenous, structurally unrelated peptides, alpha melanocyte stimulating hormone (a-MSH; anorectic) and agouti related protein (AGRP; orexigenic), interact with MC receptors (MCR) to reciprocally regulate intake. For these peptides, the proposed mechanisms of their action on MCRs have been controversial. MCR pharmacology has only been evaluated in melanoma cells or in cells transfected with various MCR subtypes. We have recently identified that murine N1E-l 15 neuroblastoma cells endogenously express the MC3R, one of the feeding-relevant receptor subtypes. Three themes within the proposal include comprehensive radioligand studies, functional analyses and receptor regulation at the MC3R in N1E-l 15 cells. The first two will serve to complement and extend upon earlier findings from non-neuronal models in terms of binding and signal transduction at this MC subtype. The third is particularly important and timely, as little is known about regulation of feeding-relevant MCRS. Given that the contribution of endogenous MCs to the regulation of intake and body weight likely arises from their chronic effects at MCRS and that any anti-obesity treatment targeting the MC system will ultimately involve long-term drug treatment, it is critical to gain insight into the effects of prolonged agonism and antagonism at these receptors.